Alcohol abuse, a major health problem in the US, is known to alter host immunity and suppress host defenses to a number of infectious agents. Ethanol is a major problem among the populations affected by HIV. However, the effects of ethanol and its metabolites on the pathogenesis of HIV infection are largely unexplored. Monocytes and macrophages are now known to be major reservoirs of HIV and it has been postulated that these cells are responsible for dissemination of HIV throughout the body, including the central nervous system. The egress of monocytes into tissues require these cells to transverse the microvessel endothelial cells that line the vasculature. In the central nervous system, this occurs across brain microvessel endothelial cells (BMEC), which constitute the blood brain barrier (BBB). Ethanol has been shown to alter the properties of both monocytes and endothelial cells. Alcohol and its metabolites may thus alter the interaction of HIV with monocytes and endothelial cells or the interaction of monocytes and endothelial cells with each other. These effects are likely to effect the pathogenesis of HIV into host tissues. Using an in vitro model of monocyte:microvessel endothelial cell interaction, this proposal will examine the effects of ethanol and its major metabolite, acetaldehyde, on the susceptibility of monocytes and endothelial cells to HIV. Because of the importance of HIV in the CNS, we will focus on the brain microvessel endothelial cells. It will also examine the effects of ethanol on the adherence and transmigration of monocytes across the endothelial lining. The broad objective of this proposal is to test the hypothesis that ethanol and/or its metabolite, acetaldehyde, alter the susceptibility of monocytes and/or microvessel endothelial cells to HIV infection and replication. Further, ethanol and its metabolites modify the interaction of normal and HIV infected monocytes with microvessel endothelial cells, thus affecting monocyte adherence and transmigration. These effects may suppress the inflammatory response or facilitate entry of HIV into tissues, thus contributing to the progression of HIV infection.